This invention relates to the use of magnesium containing products for the therapy and the prophylaxis of neoplastic and autoimmune diseases. More specifically, this invention relates to the use of magnesium, in the form of magnesium salts or complexes, or in any other form suitable for releasing Mg++ ions, for the production of drugs to be administered against neoplastic or autoimmune diseases, both for prophylaxis and for therapy purposes.
It is known that magnesium is a natural element widely diffused in living organisms, specially in mammals, wherein the largest concentration thereof occurs in bones. In humans, about 60% of the total amount of magnesium is stored in the bone tissues, about 34% in the soft tissues and about 5% in the intercellular spaces. It is also well known that magnesium, being a normal component of the blood plasma and a calcium antagonist, takes part in the muscle contraction mechanism and is vital for the action of a number of enzymes.
The daily magnesium requirement for humans ranges from 5 to 10 mg/per kg of body weight, and is normally supplied through the food, particularly vegetables. A magnesium deficiency in a living organism could be associated to abnormal muscle excitability as well as convulsions. This can occur in babies from birth, when the mother was already depleted of her own magnesium reserves, or when the baby is poorly supplied with magnesium, and/or undergoes high magnesium losses from his or her organism. When encountered in an adolescent, adult or aged person, a magnesium deficiency can be ascribed to generally stressing conditions, chronic intoxication or disease, to misabsorption, to alcohol or drugs abuse, as well as to hormone pathologies that cause magnesium losses for long time periods. More specifically, a magnesium deficiency referable to a poor supply can be due, e.g., to growth, pregnancy, breast feeding, anorexia, vomiting, overload of calcium, of vitamin D, of phosphorus, of alkalizing products, or to excessive intake of alimentary fibre, to low calorie diets, to alcoholism, etc. A magnesium deficiency referable to defects in magnesium metabolism can be due, e.g., to stress or neurosis, to nervous disorders or to endocrine-metabolic disorders (J. Durlach, xe2x80x9cIl magnesio nella pratica clinicaxe2x80x9d, p. 118 and foll., IPSA, Palermo (1988)).
A magnesium deficiency or excess in an organism cannot be quantified as an absolute value, as the magnesium level in the blood is not related with the presence thereof in the deposit sites mentioned above. Generally speaking, the means for detecting the magnesium body contents include the detection of blood levels of magnesium, in the patient""s plasma or in the serum (whose anomalies generally indicate a disorder in magnesium metabolism and are, normally, the starting point for a set of further specific tests); the detection of magnesium levels in the urine (which gives a measure of the elimination of magnesium via urine, and is normally associated with protein intake, being the Mg/urea ratio in the urine quite constant); the detection of magnesium levels in the spinal fluid; the detection of erythrocytic magnesium (which shows the amount of Mg contained in the bone marrow when erythropoiesis occurs and allows, therefore, an indirect medullary exploration as concerns magnesiumxe2x80x94it is to be noted, however, that the erythrocytic magnesium level is a function of the erythrocyte age and, accordingly, a quick erythrocyte renewal is associated with an erythtocytic magnesium increase, without any reference to any magnesium excess); the detection of lymphocytic magnesium; nuclear magnetic resonance with 25Mg (which evidences any modifications in the subcellular distribution of magnesium and in the different chemical-physical structures); and, finally, the detection of magnesium contents in the patient""s bones and muscles.
According to the current medical opinion, the administration of magnesium would promote the growth of established solid tumours and generally the worsening of autoimmune diseases (see, e.g., J. Durlach, p. 215-216, cited above). Such opinion is based on the finding that erythrocytic magnesium increases when a tumour is under development or when a chronic disease, such as for example hepatic cirrhosis, shows a malignant degeneration, or when an autoimmune disease shows a recrudescence. Furthermore, the erythrocytic magnesium level would decrease when these diseases are under remission.
Specifically, at the onset of a tumoral or of an autoimmune disease a magnesium depletion takes place throughout the organism, together with a simultaneous transfer of said element from the bone marrow to the newly formed erythrocytes, and with a massive transfer of said element, carried out by the erythrocytes, to the tumoral areas or to the areas affected by the autoimmune disease. In all cases, a magnesium increase in the blood is detected. In view of that, according to the current medical opinion magnesium is the xe2x80x9cfuelxe2x80x9d used by the tumour or autoimmune disease to progress.
Accordingly, the conventional therapies use immunosupressants to treat autoimmune diseases and antineoplastic chemotherapy agents to treat tumoral diseases, i.e. they use drugs aimed at reducing the cell mitotic activity in so far as it is more accelerated. These drugs actually slow down the cell metabolism (thus acting more on the affected cells than on the healthy cells), but they also cause a drastic magnesium depletion throughout the organism.
The theory according to which a solid tumoral disease can be made to regress by depleting the magnesium contents in an organism was confirmed by the findings of Parson and colleagues in 1974 (F. M. Parson et al., xe2x80x9cRegression of malignant tumours in magnesium and potassium depletion induced by diet and haemodialysisxe2x80x9d, The Lancet, Feb. 16, 1974), who obtained a partial regression of neoplastic lesions in some xe2x80x9cend-stagexe2x80x9d patients by inducing a forced magnesium depletion throughout the organism. Said depletion had been obtained by combining an almost magnesium free diet with a haemodialysis procedure, through which a high amount of magnesium was removed daily from the patient.
The validity of this therapeutic approach seems not to have been confirmed after such first attempts; however, up to now the leading medical opinion considers the admistration of magnesium as a harmful measure in respect of most neoplastic diseases and of autoimmune diseases.
According to the theory underlying the present invention, on the contrary, it has now been found that, both in man and in animals, a magnesium deficiency can actually be the origin of pathologies which are ascribable both to an excess and to a deficiency of the immune response. As it is well known, in the case of an excess of immune response, the organism shows a reactivity alteration which results in its generating autoimmune antibodies (i.e., antibodies against some components of the same generating organism), thus developing autoimmune diseases. In the case of a deficiency of said response, on the other hand, tumors or diseases from viral, bacterial, parasitic or fungal agents, that the organism is unable to defeat, could arise.
According to this invention, whether an organism depleted of magnesium shows the first or the second reaction mentioned above depends upon the variability of the genome of any single individual. Said variability makes the immune system behave hypo- or hyper-reactively according to the individual diathesis. In both cases, however, the occurrence or progression of a disease, which is the result of an inadequate immune response, has as its starting cause a magnesium deficiency.
By taking specifically into account the neoplastic diseases, it is well known that a human or animal organism generates daily about twenty tumoral cells as average. Such cells are normally recognized by the immune system as a foreign substance, on the basis of the detection of their altered gene sequences, and are then removed. When this does not occur and the immune mechanism is slowed down or made ineffective because of a magnesium deficiency, the malignant cells (poorly differentiated or even not differentiated at all, but very aggressive and not mutually bound, due to the absence of an intercellular bonding substance) develop, then overwhelming the ability of the hosting organism, the survival of which depends upon maintaining a very high differentiation level of the cell patrimony.
As to the autoimmune diseases, the difference with respect to tumoral diseases consists in the fact that in this case (which occurs in alternative to the case of tumoral diseases owing to the individual genome difference, as pointed out above) the immune system shows, instead of being hypoergic, a form of hyperactivity not intended at defending the organism, but directed against some components of the same, recognized as foreign substances. Unavoidably, this mechanism leads to a form of self-cannibalism.
In all cases, a possible latency of a disease induced by a magnesium deficiency depends mainly from the quality of the constitutional or acquired homeostatic mechanisms, of a general nature or specific for the magnesium regulation. Said quality vary from one individual to another, and it is obvious that the individual tolerance of a chronic magnesium depletion is different from one case to another, according to the quality of the magnesium homeostasis. Anyway, it is a general opinion that decompensation factors are required to cause the appearance of a symptomatology.
In view of the foregoing, according to this invention there is proposed to use magnesium, or preferably any physiologically acceptable source of Mg++ ion, to treat solid tumoral diseases, as well as to prevent and treat autoimmune diseases.
Magnesium-containing products in the form of organic or inorganic salts, or in the form of magnesium ion complexes, are already used in therapy, mainly as antacids, laxative and purgative preparations, but also as metabolism regulators, anticonvulsants and sedatives. Obviously, it should be noted that not in all of the active substances containing magnesium ions the latter perform a true therapeutic function. In the case of magnesium sulfate, for instance, it is ackowledged that the laxative action is rather due to the osmotic conditions of the solutions employed and to the typical function of the sulfate anion, than to the properties of the magnesium ion. Therefore, the new medical indications according to this invention can be put into practice by using any magnesium compound which is able to supply the organism with Mg++ ions in absorbable form, and which does not show further therapeutic activities incompatible with the activity considered by this invention.
Thus, the present invention specifically provides the use of a pharmaceutically acceptable magnesium salt or complex in the manufacture of a medicament for the therapy of solid neoplastic diseases and for the therapy and/or the prophylaxis of autoimmune diseases.
The pathologies that, according to the invention, are considered to be new indications of the magnesium therapy are, in the field of the neoplastic diseases the solid neoplasies (i.e., organ neoplasies) and, in the field of the autoimmune diseases, any so properly called disease, as well as any diseases showing an autoimmune mechanism. The so-called autoimmune diseases comprise rheumatoid arthritis, local and systemic scleroderma, systemic lupus erythematosus, discoid lupus erythematosus and cutaneous lupus, dermatomyositis and polymyositis, Sjxc3x6gren""s syndrome, nodular panarteritis, autoimmune enteropathy, proliferative glomerulonephritis, active chronic hepatitis and the polyglandular deficiency autoimmune syndrome type 1 and 2. The diseases that involve anyhow an autoimmune mechanism comprise multiple sclerosis, pemphigus vulgaris and pemphigoids, psoriasis and parapsoriasis, intestine inflammatory diseases such as the ulcerative colitis and the Chron""s disease, vitiligo and sarcoidosis.
The conventional therapies for the above diseases widely vary, ranging from surgery to irradiation and physiotherapic treatments, and in most cases, to chemotherapy, using a number of different active substances, among which cortisone, immunosuppressants, interferone and cortico-steroids. On the contrary, according to this invention, all of the above pathologies are to be connected with a more or less severe magnesium deficiency, which results in either an unsuitably weak or in an excessively strong immune response. Thus, a proper magnesium therapy, optionally but not necessarily associated with conventional treatments, can bring the organism to restore the correct functions of the immune system and, consequently, to defeat the above pathologies.
As to the mechanism of action, it is believed that magnesium therapy, by restoring the optimal magnesium levels, leads the immune system to increase the production of the Th1 sub-population of T-helper lymphocytes, thus increasing the cell-mediated immune system response. Actually, it is well known that Th1 lymphocytes mainly secrete interleukin 2 and gamma interferon, and that these cytokines stimulate a cell-mediated response, that removes the infected elements from the organism (Mossmann and Coffmann, DNAX Research Institute, Palo Alto, Calif.).